Tuberculosis (TB) is a bacterial disease caused by Mycobacterium tuberculosis and that has a major public health impact, but for which treatment is difficult and protracted. Thus, significant efforts are devoted to the development of new anti-TB drugs and treatment regimens. A major impediment in obtaining new anti-TB drugs is the difficulty and cost in performing clinical trials. South Africa is not only a region endemic for TB but is also a country that has become a focus of clinical research and clinical trials. Our strong preliminary evidence based on peripheral blood transcriptome, proteome, metabolome and host cellular immune responses during different stages and outcomes of TB treatment, including multi- and paucibacillary states provide support for the innovative hypothesis that reprogramming of the immune and metabolic responses occurs during TB treatment. This reprogramming differs among TB patients based on their response to treatment, and thus allows for the identification of distinguishing biomarkers for rapid vs. slow response, failed treatment and relapse. The proposed ICIDR project establishes a consortium of South African and US scientists with expertise in clinical and basic research to address the development of biomarkers and biosignatures to better monitor and predict treatment outcome during clinical trials. This work will be performed with existing clinical samples and those being collected form ongoing clinical studies in South Africa. It will integrate data from various omic based analytical platforms being applied in South Africa and the US to identify perturbed biological pathways representative of the paucibacillary states encountered during TB treatment. Additionally, we will link to an existing South African post-treatment vaccine clinical trail Clinical Development of a Therapeutic Vaccine for Tuberculosis funded through the Wellcome Trust to allow prospective collection of samples that can be used to test and validate biomarkers and signatures of treatment response. Thus, this project proposes to develop new tools that can be applied to a significant public health problem in South Africa and that will enhance the performance of clinical trials of new anti-TB drugs in this country and elsewhere. Moreover, the proposed research provides extraordinary training opportunities for South African scientists to integrate state-of-the-art basic science with outcome driven clinical research programs.